The present invention relates to processes and intermediates useful in the production of asenapine and related compounds.
Asenapine, trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of the formula (1)
is a compound having CNS-depressant activity (see Boer et al, Drugs of the Future, 18(12), 1117-1123, 1993) and may be used in the treatment of depression (WO 99/32108). The compound corresponding to the above formula is a trans-racemate. Both enantiomers within this racemate contribute equally to the clinical effect of asenapine. In pharmaceutical compositions, particularly intended for sublingual and buccal administration, the asenapine as defined above may be advantageously used as the maleate salt (WO 95/23600). Physico-chemical properties of the drug substance have been reported by Funke et al. (Arzneim.-Forsch/Drug Res., 40,536-539, 1990).
Asenapine is a specific example from a class of pharmaceutically active compounds,
that was disclosed in U.S. Pat. No. 4,145,434. General methodology for the preparation of asenapine is also described therein.
The synthetic approach derivable from the teaching of the U.S. Pat. No. 4,145,434 and disclosed in full in Example 9 of EP 1710241 is shown in the following scheme.

For preparing Asenapine from the acid (2), the carboxyl group is first transformed into the corresponding acid chloride by treatment with thionylchloride. Coupling with sarcosinemethyl ester provides for an ester (3). Treatment of the ester (3) with potassium tert-butoxide in toluene yields the cyclic dione (4), which is subjected to further ring closure to an enamide (5) by treatment with polyphosphoric acid.
The step of reducing the enamide (5) with magnesium in methanol gave a mixture of cis and trans lactam (6). Both isomers must be separated by column chromatography. It appears that the formation of the cis-lactam (6) is predominant (approx. 4:1 cis/trans). After separation, reduction of the cis or trans lactam (6) with LiAlH4/AlCl3 finally furnished the cis amine (1a) or desired trans amine (Asenapine), respectively. Because the cis isomer is predominant, the synthesis is not optimal.
An alternative synthetic route proceeds via the compound (6a),
which is the regio-isomer of the compound (6) and which may be reduced to asenapine similarly as the compound (6). A suitable way for making (6a) may be similar to the process of making (6), i.e. is based on the reduction of the enamide (5a)
which, in turn, may be prepared in an analogous process as disclosed above, starting with the corresponding regioisomer of the compound (2); namely the compound (2a)
(see Vader et al., J. Labelled Comp., Radiopharm., 34, 845-869, 1994). Similarly as the conversion of (5) to (6), the conversion of (5a) to (6a) yields predominantly the undesired cis-isomer.
An alternate way of making the compound (6a) has been described in Example 8 of the EP 1710241 (US 2006/0229352, WO 2006/106136)

It seems from the disclosure that this reaction exhibits good yields, but it also predominantly provides the unwanted cis-isomer of the compound (6a) upon subsequent work up, which leads consequently to the cis-asenapine (1a).
According to EP '241, the unfavourable product ratio may be improved by subsequent partial isomerization of the unwanted cis-isomer of the lactam (6) or (6a) into the trans-lactam using 1,5-diazabicyclo[4,3,0]non-5-ene (DBN), yielding an trans-cis equilibrium in approx. 1:2 ratio. Repeated isomerization may provide an overall 38% yield of the trans-(6) isomer, starting from the enamide (5).
The formation of the desired trans-isomer of the amide (6) or (6a) in low relative amounts is a serious disadvantage in the above-mentioned asenapine processes. Its amount may be enhanced by a partial racemization as indicated above. But the cis-amide apparently is thermodynamically more stable isomer than the trans-amide, so that a racemization as a possible way how to enhance the yield of the desired trans-amide (6) is not a particularly effective solution. Another problem arises with the separation of the trans amide from the cis amide. Even by using of column chromatography, a pure trans-isomer is difficult to be obtained.
An attempt to solve the problem was disclosed in EP 1710241. The cis-trans mixture of the compound (6) and/or its regio-isomer (6a), preferably without separating the enantiomers, undergoes the ring-opening reaction by an excess of strong base in an alcoholic medium, wherein it was found that predominantly a trans-isomer of the amino/ester of the formula (7) and/or of the formula (7a) may be formed
in an approx. ratio 10:1 (trans: cis). The trans-(7) or the trans-(7a) may be isolated and subjected to re-cyclization yielding the desired trans-(6) or trans-(6a) with the overall yield of about 60% in respect to the compound (5). More advantageously, the trans-compound (7) or (7a) may be converted to asenapine directly, by a cyclization by treating with a reducing agent, optionally with a combination with a Lewis acid.
It would be desirable to find an alternative route to make asenapine and/or trans intermediates thereof in good isomeric purity. It would also be desirable to have a process that could be applied to making other related trans-configuration compounds such as those described in U.S. Pat. No. 4,145,434.